Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma.

Research output: Contribution to journalArticle

Abstract

Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin B-cell lymphoma with poor prognosis due to drug resistance. Introduction of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has markedly improved MCL therapy outcome, but drug resistance remains a challenge. The selective cell-surface expression of oncogenic receptor tyrosine kinase–like orphan receptor 1 (ROR1) pseudokinase in hematological malignancies has made this receptor a promising candidate for targeted therapy. We sought to identify the molecular mechanism underlying divergent ROR1-mediated apoptotic responses in MCL cell lines and primary samples. We show that targeting ROR1 expression resulted in downregulation of NF-κB p65 levels and that activation of the NF-κB pathway can antagonize ROR1-mediated apoptotic responses. High-throughput drug-sensitivity testing of MCL cells before and after ROR1 targeting revealed synergistic effects between cotargeting of ROR1 and the B-cell antigen receptor (BCR) or Bcl-2 family, underlining the high potential for ROR1-targeted therapies in overcoming MCL drug resistance. However, inhibition of the BCR pathway by targeted drugs such as ibrutinib can impair ROR1 expression and consequently ROR1-targeted treatments, underscoring the importance of inhibiting both pathways to augment cancer cell killing. Considering the central role of NF-κB pathway activation in B-cell malignancies, this study highlights key factors that can modulate ROR1-targeted treatments in hematological cancers.

Details

Authors
  • Hanna Karvonen
  • David Chiron
  • Wilhelmiina Niininen
  • Sara Ek
  • Mats Jerkeman
  • Elaheh Moradi
  • Matti Nykter
  • Caroline A. Heckman
  • Olli Kallioniemi
  • Astrid Murumägi
  • Daniela Ungureanu
Organisations
External organisations
  • University of Tampere
  • University of Nantes
  • Nantes University Hospital
  • University of Helsinki
  • Karolinska Institutet
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageSwedish
Pages (from-to)2257-2268
JournalBlood Advances
Volume1
Issue number24
Publication statusPublished - 2017 Nov 9
Publication categoryResearch
Peer-reviewedYes